Abstract: Background & aims The only curative treatment of CML to date, remains allogeneic stem cell transplantation (Allo-SCT) despite some observations of non-detectable disease recurrence after tyrosine kinase inhibitor (TKI) cessation. The scope of allogeneic stem cell transplant for chronic phase (CP-) CML remains debatable and it seems interesting to retrospectively analyse the settings of this procedure in such patients since the introduction of TKI within the therapeutic arsenal of this disease. Methods We retrospectively analysed the registry of the Francophone society of stem cell transplantation and cellular therapy (SFGM-TC) from 2002 to 2014, for patients being in CP at diagnosis and at transplant. All data were captured according to thefrench regulations and were collected after signed up informed consent for each patient. All patients were transplanted for different degrees of resistance or severe recurrent intolerance to TKI(s). We segmented the observation period into two parts: 2002-2006 (Imatinib era) and 2006-2014, once second generation TKI were available in our country (TKI2 era). All patients were in CP-CML at diagnosis and first chronic phase at transplant. Second transplants for the same patient were excluded from this analysis. Results From 2002 to 2014 the proportion of transplants for CML dramatically decreased form 7.1% to 〈 3% of totalallo-SCT performed in the country. Nevertheless, between 2002 and 2014, 191 transplants were performed for CP-CML, 121 during the first period and 70 during the second period. Interestingly, age at transplant is 36 (26-43) for IM period and older, 44 (26-55) years for TKI2 period; with a sex ratio of 1.08 and 1.3 respectively (p=ns). The median interval between diagnosis and transplant was 19 (1.4-197) months for IM period and much longer thereafter[32 (6.6-194) months, p 〈 0.001]. The source of cells varied a lot with 71% of BM, 25.5% PBSC and 3.5% CB for IM period, 37% BM, 56% PBSC and 7% CB for TKI2 period (p 〈 0.001), whereas the proportion of MAC versus RIC remained stable (88.5%/11.5% versus 81%/19%, p=0.262). The use of TBI as a part of the conditioning regimen was drastically reduced during the second period: 37% IM era, 14% TKI2 era (p 〈 001). While ABO match did not differ, the use of unrelated donors largely increased in the second period (66% versus 46%, p=0.015), with less identical sibling donors used (33% versus 52%) in this last period. The proportion of sex match did not differ with a majority of male to male transplants (28% and 37%; p=ns) performed in both groups. The majority of patients wereGratwohlscore 3 in IM period andGratwohlscore 4 in the second period. Overall, the cumulative incidence of grade 2-4 acute GVHD was 32%, 41.3% and 44% at 1,2 and 3 months respectively, and the overall cumulative incidence of chronic GVHD was 26%, 40%, 45%, 50% at 1, 2, 5, and 10 years. The TRM rates were not different between the 2 periods: 22.4%, 23%, 26.65% and 27.8% at 1, 2, 5 and 10 years for IM period and 16.2%, 19.7%, 22.4% and 27.8% at 1, 2, 5 years for TKI2 period (NR 10 year for this period, p=0.508).The overall (OS) and relapse-free survival (RFS) rates according to the two periods are shown in Figure 1, with only a trend in the improvement of OS and RFS in the TKI2 period (log-rank tests, p=0.601 and 0.651 respectively).Gratwohlscore efficiently segregated patients for OS (overall p value = 0.002) and RFS (p=0.007). Multivariate analysis adjusted on OS identified only age (HR=1.02, p=0.05), and a related donor as a favourable variable on outcome (HR=0.53, p=0.031) with no significant influence of age, interval diagnosis-allo-SCT, source of donor cells, and type of conditioning regimen. Conclusion Allo-SCT still remains a curative treatment of CP-CML despite significant toxicities over time and the picture of this procedure in the therapeutic arsenal has dramatically changed over the last decade due to multiple therapeutic options offered now. Despiteallo-SCT of patients with longer diseases histories, probably more co-morbidities, there is an encouraging trend in the improvement of OS and RFS. Figure 1 OS and RFS for CP-CML according to the engraftment period. Figure 1. OS and RFS for CP-CML according to the engraftment period. Figure 2 Figure 2. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Coiteux:Novartis, BMS, ARIAD: Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Abstract: Introduction Failure to respond to steroid therapy for intestinal acute graft-versus-host disease (aGvHD) is associated with limited further therapeutic options. Fecal microbiotherapy is defined as the perfusion of treated stool from one or several healthy donors via the upper or lower gastrointestinal (GI) route aiming at improving microbial diversity and functionality. Here we report clinical outcomes from a 76-patient cohort with steroid refractory (SR) GI-aGvHD treated with the pooled allogenic fecal microbiotherapeutic MaaT013. Twenty-four patients were treated in the prospective, single-arm, phase IIa, HERACLES study (NCT03359980) while 52 patients were treated in an expanded access program (EAP). Patients and methods For HERACLES, 24 patients with grade III-IV SR-GI-aGvHD were treated with MaaT013 in 26 European sites, as a 2 nd line therapy after SR diagnosis and evaluable for treatment response. In EAP, 52 patients with steroid-dependent or SR-GI-aGvHD (classical n=41, late onset n=3, overlap syndrome n=8) were treated. These patients had previously received and failed 1 to 6 lines (median 3; 40/52 received ruxolitinib) of GvHD systemic treatments. GI-GvHD response was evaluated weekly and 28 days after day (D) 0 (inclusion for HERACLES or 1st dose for EAP). For all patients, GI-overall response rate (ORR) at D28 was defined as the proportion of patients achieving complete response (CR), very good partial response (VGPR) or partial response (PR), compared to D0, without the use of additional systemic therapy. Other endpoints included the best overall response (BOR) achieved at any time, and overall survival (OS). Prepared under GMP, MaaT013 is characterized by a highly consistent richness of 455 ±3% OTUs and an Inverse Simpson index & gt; 20. Treatment comprised 3 MaaT013 doses, each composed of 30 g of feces in 150 mL volume of inoculum (total 90 g of feces from 4 to 8 healthy donors) administered by enema (except for 2 EAP patients by nasogastric tube). All patients received at least 1 MaaT013 dose, 92% (HERACLES) and 87% (EAP) at least 2 doses, and 50% (HERACLES) and 71% (EAP) the full treatment course. In HERACLES, the reasons for not applying the 3 rd dose were death (n=5), physician decision to introduce salvage therapy (n=5), and ICU hospitalization (n=2)). Results In HERACLES, the GI-ORR was 38% including 5 CR, 2 VGPR and 2 PR. In EAP, positive GI-response was achieved in 31/52 patients (60% with 16 CR, 11 VGPR and 4 PR). Considering the GI-BOR, 13/24 (54%) and 35/52 (67%) achieved at least a PR in HERACLES and EAP respectively. In HERACLES, OS was 29% at month (M) 6 and 25% at M12. OS was significantly higher in responding (R) patients (achieving at least PR at D28) compared to non-responding (NR) (44% vs 20% at M6 and 44% vs 13% at M12, logrank p=0.047). In EAP, OS was 48% at M6 and 37% at M12, and significantly higher in R patients compared to NR (71% vs 17% at M6 and 62% vs 6% at M12, logrank p & lt;0.0001). In HERACLES, treatment with MaaT013 was characterized by excellent tolerance: 252 Treatment-Emergent Adverse Events (TEAE) were reported for the 24 patients, the majority being infections (79%) and GI disorders (62%), as expected in GvHD patients. Of these 252 TEAE, only 2% (5 serious events in 2 patients) could not reasonably be excluded from being related to MaaT013 by the investigators. Shotgun sequencing in these 5 TEAE revealed that the causative infectious agents could not be detected in the administered MaaT013. In EAP, the safety profile of MaaT013 was considered satisfactory for all patients. 16S microbiome analyses were performed in the HERACLES population and showed that MaaT013 produced an early increase in α-diversity at genus level with a significant increase in Richness index at all evaluated timepoints (p & lt;0.003). At D28, R patients had higher values of α-diversity indices (Shannon p=0.005 and Richness p=0.038) compared to NR patients, and higher proportions of MaaT013-derived species in the total composition of R microbiota (p=0.043). Conclusion We herein report the treatment of 76 SR-GI-aGvHD patients using a full ecosystem, pooled-donor, high-richness biotherapeutic. The D28 GI-ORR was 38% and 60% in HERACLES and EAP respectively and this clinical benefit positively and significantly impacted OS (44% and 62% M12 in HERACLES and EAP R patients respectively). MaaT013 was shown to be safe and effective in these heavily immunocompromised patients, warranting further exploration of this approach. Figure 1 Figure 1. Disclosures Malard: JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Astellas: Honoraria; Biocodex: Honoraria; Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria. Loschi: CELGENE/BMS: Honoraria; AbbVie: Ended employment in the past 24 months, Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Cluzeau: Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Takeda: Other: travel, accommodations, expenses. Huynh: Jazz Pharmaceuticals: Honoraria. Holler: MaaT Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vehreschild: SocraTec R & D GmbH: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Takeda Pharmaceutical: Research Funding; Seres Therapeutics: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; 3M: Research Funding. Gasc: MaaT Pharma: Current Employment. Plantamura: MaaT Pharma: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Abstract: In adult ALL, oncogenetic markers and minimal residual disease levels are independent outcome predictors. Both factors should be used for individual treatment stratification.

Abstract: Rational: The significant increase in haplo-identical allogeneic cell transplantation (Allo-HCT) has led to the more frequent use of cyclophosphamide (Cy) after transplantation for graft-versus-host disease (GVHD) prophylaxis (PT-Cy). This strategy has subsequently been used in related and unrelated allogeneic HCT settings as well with some controversial results. Patients and Methods: We analyzed all consecutive Allo-HCTs from matched related (MR) and unrelated donors (HLA matched and mismatched: MUD and MMUD) reported to the SFGM-TC registry from January 2014 to December 2019 and who have received PT-Cy alone or in combination with other immunosuppressive molecules (IS). We therefore performed a pair-matched analysis (1/2) with transplantations using classic GVHD prophylaxis with (w) or without (wo) anti-thymocyte globulins (ATG). The primary objective was to evaluate the incidence and severity of acute and chronic GVHD in PT-Cy compared to other strategies. Secondary objectives included: modalities of PT-Cy and IS, cumulative incidence of relapse (CIR), non-relapse mortality (NRM), overall survival (OS), GVHD and relapse free-survival (GRFS), infection rates. Results: We analyzed a total of 1190 patients (pts), 386 (32%) received PT-Cy and matched with 804 (68%) pts who received classic GVHD prophylaxis (no PT-Cy). Among PT-Cy patients, 59% were males with a median age of 55.3 years (3.4-75.5), 49% were AML, 14% ALL, 20% MDS and MPS, 12.5% NHL and HL, and 4.5% Multiple Myeloma. Before transplantation, 61% of pts were in complete remission (CR), 34% not in CR, 2% in stable disease and 3% were not treated. Conditioning regimen was myeloablative in 35% of patients, 86% received peripheral blood stem cells, 31% were CMV negative pairs, 58% were sex-matched and 51% were ABO compatible. There was no significant difference between the PT-Cy and no PT-Cy groups regarding all the variables. We identified four groups: group 1: PT-Cy + IS (n=259), group 2: PT-Cy + ATG + IS (n=120), group 3: ATG w or wo IS (n=651) and group 4: other IS (n=160). We observed significant differences between the 4 groups for age (p & lt;0.001), type of disease (p & lt;0.001), disease status (p=0.016), conditioning intensity (p=0.002), HC source (p & lt;0.001), HLA matching (p & lt;0.001) and ABO compatibility (p & lt;0.001). The cumulative incidence of acute GVHD grades II, III/IV, chronic GVHD, relapse and NRM, the probability of OS and GRFS are shown in Table 1. The results of multivariate analysis (Table 2) showed a significant lower incidence of acute GVHD gr II, III, IV and chronic GVHD after PT-Cy + IS and a significant higher TRM after ATG ± IS. In addition, other well-known parameters were found to have a significant impact as age on OS and GRFS, use of unrelated donor on OS and CIR and PBSC on chronic GVHD. Regarding severe infections after HCT, there was no difference between PT-cy and pair-matched patients except for pneumonia (12.5% vs. 8% respectively, p=0.08) and septicemia (12% vs. 1.7% respectively, p & lt;0.001). In conclusion, there was a significant lower incidence and severity of acute and chronic GVHD in the PT-Cy group after related, HLA matched and mismatched unrelated Allo-HCT compared to matched patients with other GVHD prophylaxis with a higher NRM when patients received ATG. We did not observe significant translation into GRFS improvement probably due to the higher toxicity of PT-Cy. Figure 1 Figure 1. Disclosures Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huynh: Jazz Pharmaceuticals: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

Abstract: Abstract 572 Aim. In recent series of adults with acute lymphoblastic leukemia (ALL), the GRAALL (ASH 2009, abstract 577) and other cooperative groups have confirmed the strong prognostic value of Ig/TCR minimal residual disease (MRD) on patient outcome. Despite this, age, WBC, CNS involvement, recurrent chromosomal translocations, and early response to steroids and chemotherapy remain frequently used to tailor post-remission therapy and envision allogeneic stem cell transplantation (SCT) in most adult ALL trials. We updated our MRD study, now with 262 patients who all achieved complete remission (CR) after the first induction and were assessed for MRD after induction (MRD1, at 6 weeks) and consolidation (MRD2, at 12 weeks). One hundred and fifty-eight patients had Philadelphia chromosome (Ph)-negative B-cell precursor ALL (BCP-ALL), while 104 had T-cell ALL (T-ALL). Since 107 of the BCP-ALL (68%) were studied for IKZF1 deletion and 90 of the T-ALL patients (87%) for NOTCH1/FBXW7 mutations, we were able to reassess the MRD significance according to these newly described oncogenic markers. These two covariates (i.e. MRD and IKZF1/NOTCH1/FBXW7 genetics) allowed us to redefine a much simpler yet more powerful stratification of disease risk in both BCP- ALL and T-ALL subsets. Methods. All 262 patients studied (median age, 31.5 years) were treated in the GRAALL-2003 and GRAALL-2005 trials. Although they were younger and had more frequently circulating blasts, other characteristics and outcome did not differ from patients treated in the same trials but not assessed for MRD. Ig/TCR MRD levels were determined according to Euro-MRD guidelines (Leukemia 2007;21:604). IKZF1 deletions were assessed by multiplex multi-fluorescent PCR. NOTCH1/FBXW7 mutations were assessed as previously described (Blood 2009;113:3918). Multivariate backward stepwise selection Cox models were used for the cumulative incidence of relapse (CIR), disease-free (DFS) and overall survival (OS) endpoints, after censoring transplanted patients at SCT. Models were always adjusted on age (35-year cutoff), WBC (30 and 100 G/L cutoff for BCP- and T-ALL, respectively), CNS involvement, and trial. Additional BCP-specific covariates included CD20 expression, t(4;11) and t(1;19) translocations, and IKZF1 deletion. Additional T-specific covariates included cortical immunophenotype according to the EGIL classification, TLX1 overexpression, and NOTCH1/FBXW7 mutation. Finally, allogeneic SCT was re-evaluated in the newly defined risk subsets, as a time-dependent covariate. Results. An initial multivariate analysis revealed that among blood response after 1 week of steroid, bone marrow response after 2 weeks of therapy, and molecular response at both MRD1 and MRD2 time-points, the MRD2 level was the main and sole independent predictor of relapse (P=0.003). In BCP-ALL patients, persistent MRD2 and IKZF1 deletion were the only two independent factors identified, the presence of at least one factor defining 51% high-risk patients with 52% versus 15% CIR (HR, 3.8; P= 0.008), 41% versus 81% DFS (HR, 3.6; P= 0.005), and 54% versus 80% OS (HR, 3.9; P= 0.015) at 4 years. Allogeneic SCT in first CR significantly decreased relapse incidence and prolonged DFS in these new high-risk BCP-ALL patients (HR, 0.23 and 0.40; P= 0.016 and 0.05, respectively). In T-ALL patients, persistent MRD2 and lack of NOTCH1/FBXW7 mutation were the only two independent factors identified, the presence of at least one factor defining 49% high-risk patients with 64% versus 12% CIR (HR, 6.4; P= 0.002), 36% versus 88% DFS (HR, 6.4; P= 0.002), and 41% versus 95% OS (HR, 7.3; P= 0.015) at 4 years. SCT had no significant effect on relapse incidence and DFS in these new high-risk T-ALL patients. Conclusion. In adult patients with Ph-negative ALL treated with the pediatric-inspired GRAALL regimen, IKZF1 deletion in BCP-ALL, NOTCH1/FBXW7 mutation in T-ALL, and MRD at 3 months in both subsets replace all classical risk factors, leading to a new simplified prognostic scoring system based only on IKZF1 and NOTCH1/FBXW7 genetics and MRD clearance. This new risk score identifies approximately half of the patients as good-risk, with a relapse incidence as low as 10–15%. It will be validated and used prospectively in the next generation of GRAALL trials, to stratify both new drug evaluation and SCT in first CR. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction. In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-identical matched sibling donor (MSD), use of cyclosporine A in association with methotrexate has been the main graft-versus-host disease (GVHD) prophylaxis strategy. Addition of antithymocyte globulin (ATG), especially when using peripheral blood stem cells (PBSC) as source, has also been shown to favor lower rates of chronic GVHD. More recently, use of post-transplant cyclophosphamide (PTCY) in the haploidentical setting resulted in low incidences of both acute and chronic GVHD. Its use has therefore been subsequently reported in other donor settings, including MSD. The aim of our study was to compare GVHD prophylaxis containing either PTCY or ATG in patients diagnosed with acute myeloid leukemia and undergoing allo-HSCT from a MSD. Methods. This was a retrospective study from the EBMT registry. Included were adult patients undergoing their first allo-HSCT during the period 2008-2018 and who were in complete remission at time of allo-HSCT. Results. Globally, 197 and 1,913 patients receiving either PTCY or ATG, respectively, were identified who fulfilled inclusion criteria. Patients in the PTCY group were younger (median age 47 versus 54 years, p & lt;0.01) and had undergone allo-HSCT more recently (median year of allo-HSCT: 2015 versus 2014, p & lt;0.01). Peripheral blood was the more frequently used stem cell source, this being significantly more frequent in the ATG group (95% versus 70%) than in the PTCY group (p & lt;0.01). The conditioning regimen was more frequently myeloablative in the PTCY group (59% versus 48% in the ATG group, p & lt;0.01). Cyclosporine-A alone was the most used systemic immunosuppressive agent associated with either PTCY (22%) or ATG (28%), while 34% and 29% of patients in the ATG group and 7% and 12% in the PTCY group also received either methotrexate or mycophenolate mofetil along with cyclosporine A. No statistical differences were observed for incidence of grade II-IV acute GVHD at 100 days after allo-HSCT, this being 19% versus 17% in the PTCY and ATG groups, respectively (p=0.81). On the other hand, a significantly higher incidence of chronic GVHD at 2 years was observed with the use of PTCY (37% versus 30%, p & lt;0.02) and for extensive chronic GVHD (16% versus 12%, p & lt;0.01) as compared to ATG. There was no impact of conditioning intensity on GVHD incidence. No statistical differences were observed on univariate analysis for all other transplant outcomes, with a leukemia-free survival (LFS) of 55% versus 58%(p=0.75), overall survival (OS) of 64% versus 65% (p=0.61), GVHD-free, relapse-free survival (GRFS) of 44% versus 49% (p=0.19), relapse incidence (RI) of 36% versus 32% (p=0.56) and non-relapse mortality (NRM) of 8% versus 10% (p=0.78). Of note, the cumulative incidences of death due to GVHD were 4.4% and 4% in the PTCY and ATG groups, respectively (p=0.53). Also, there were no differences between the 2 groups for death due to infections: 6% in the PTCY group and 6.3% in the ATG group, respectively (p=0.49). On multivariate analysis, these results were confirmed, with a higher risk of chronic GVHD of any grade (HR=1.41, 95%CI 1.03-1.92; p & lt;0.01) and extensive chronic GVHD (HR=1.68, 95%CI, 1.07-2.62; p & lt;0.01) with PTCY, and no differences with respect to the other outcomes. We also observed that, regardless of the use of PTCY or ATG, use of PBSC was associated with lower RI (HR=0.64, 95% CI 0.46-0.89; p & lt;0.01), higher LFS (HR=0.71, 95% CI 0.53-0.95; p & lt;0.03), and OS (HR=0.72, 95% CI 0.52-0.99; p & lt;0.05). On the other hand, we found no statistical differences in terms of both acute GVHD (HR=0.73, 95%CI, 0.48-1.12; p=0.15) and chronic GVHD (HR=0.83, 95% CI 0.56-1.21; p=0.33) according to stem cell source. These results were also confirmed in a matched-pair analysis. Conclusion. In conclusion, our results highlight that in the HLA-identical sibling setting, the use of ATG provides similar outcomes to those seen with PTCY except for chronic GVHD for which a protective effect of ATG is confirmed as previously reported by different other studies. Disclosures Blaise: Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Abstract: Patients with t-MN have a poor prognosis with median overall survival & lt; 1 year due to high risk features of the disease and refractoriness to chemotherapy. HSCT represents the only curative treatment. Outcome after HSCT has progressively improved over time with a last EBMT study showing a 2-year OS at 44% in patients with secondary leukemia (79% post MPN or MDS) (BBMT 2018: 1406). Previous large studies showed survival & lt; 30% in patients transplanted for t-MN (Blood. 2010:1850; Haematologica 2009:542). We recently reported in patients transplanted for a leukemia arising from MDS, MPN and CMML that the primary disease impacts the outcome, particularly patients with a previous MPN had the worst outcome (BJH, 2019: 725). We report here outcome of patients who received HSCT for a t-MN (excluding post MDS, MPN and CMML) with the hypothesis that the primary cancer impacts the outcome. From EBMT registry, patients with MDS or AML occurring after a primary cancer who received a HSCT between 01/06 and 12/16 were included. OS and RFS were analyzed using Kaplan Meier curves and log-rank test, relapse and NRM were analyzed as competing risks with cumulative incidence curves and Gray's test. 2334 patients were identified. Primary cancers were CLL in 102, non-Hodgkin lymphoma (NHL) in 668, Hodgkin lymphoma (HL) in 235, plasma cell disease (PCD) in 111, breast cancer in 643 and other solid tumor (ST) in 575. 981 patients had MDS and 1353 had AML at time of transplantation. Performance status by Karnofsky score was 90 or higher in 1376 (59%) patients. 722 (31%) patients were transplanted from HLA matched sibling donor (SIB) and 843 (36%) received a myelo-ablative conditioning regimen (MAC). 1307 patients were in remission at time of transplantation: 29% of MDS and 76% of AML patients. Three-year OS and RFS were 34 and 32% respectively. OS was significantly better in patients with AML in CR (43%) than not in CR (21%). OS and DFS were impacted by the primary cancer: post NHL (30 and 27%), post HL (29 and 28%), post ST (34% for both), post breast cancer (41 and 37%), post CLL (34 and 31%) and post PCD (32 and 25%) (p & lt;0.001). CR status at HSCT did not impact outcome in MDS patients (30%). Patients with normal cytogenetics (n=397) had a better OS than patients with abnormal cytogenetics (n=1036) (43% vs. 33%, p & lt;0.001). OS was significantly better using SIB (38% vs 32%, p=0.05) and in patients with better Karnofsky score (38 vs. 28%, p & lt;0.01). NRM was lower in patients with breast cancer (24% post breast cancer, 36% post NHL, 33% post HL, 29% post ST, 34% post CLL, 26% post PCD p & lt;0.001). NRM was higher after non SIB (34% vs 23%, p & lt;0.001) and after MAC (33 vs. 23%, p & lt;0.001). Relapse rate was higher after RIC (33 vs. 28%, p=0.014) but was not influenced by the primary type of cancer. The multiple variables models includes age, regimen intensity, donor type, Karnofsky score, t-MN category (AML in CR, AML not in CR, MDS) and the primary type of cancer. Patients with HL (HR: 1.36, p=0.005) or NHL (HR: 1.31, p=0.001) had a higher adjusted risk for OS than patients with other primary diseases. Other risk factors for OS were t-MN type (AML not in CR, HR: 1.45, AML in CR, HR: 0.76, MDS = reference, p & lt;0.001), type of donor (no SIB, HR: 1.20, p=0.004) and performance status (karnofsky & lt; 90, HR: 1.34, p & lt;0.001). Patients with HL (HR: 1.24, p=0.05) or NHL (HR: 1.21, p=0.01) had also a higher adjusted risk for DFS than patients with other diseases. Other risk factors for DFS were t-MN (AML not in CR, HR: 1.42, AML in CR: HR:0.76, p & lt;0.001) and performance status (HR: 1.24, p & lt;0.001). Adjusted post-HSCT t-MN relapse risk was not influenced by the primary cancer but was influenced by age (HR: 0.92, p=0.02), MAC (HR: 0.76, p=0.002), t-MN (AML not in CR, HR: 1.51, p & lt;0.001; AML in CR, HR:0.74, p=0.03) and performance status (HR: 1.28, p=0.002). NRM risk was significantly higher in patients with NHL (HR: 1.52, p & lt;0.001), HL (HR:1.58, p=0.007) and CLL (HR: 1.55, p=0.039) than in patients with primary solid tumor or PCD. Other risk factors for NRM were age (HR: 1.15, p=0.01), MAC (1.29, p=0.006), t-MN (AML in CR, HR: 0.76, p=0.005; AML not in CR, HR:1.29, p=0.05), performance status (HR: 1.22, p=0.03). Conclusion: A quarter to one third of patients with t-MN can be cured by HSCT which was influenced by type of t-MN and performance status. The type of primary cancer influenced also the outcome with lower mortality, especially NRM in patients with previous solid tumor or PCD as compared to patients with lymphoma. Disclosures Robin: Novartis Neovii: Research Funding. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Kroeger:DKMS: Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Sanofi-Aventis: Honoraria; Novartis: Honoraria, Research Funding; Medac: Honoraria. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Chevallier:Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

Abstract: Background: Optimization of transplantation modalities (Graft versus host disease (GVHD) prophylaxis, conditioning regimens, high level HLA typing and supportive care) has improved overall survival (OS) of patients (pts) with idiopathic severe aplastic anemia (SAA) undergoing matched related (MRD) or 10/10 unrelated donor (MUD) allogeneic transplantation (HSCT). OS is nowadays of more than 80% and thus may not be sufficient anymore to accurately assess outcome. New composite endpoints including surrogate markers of quality of life, such as GVHD, may fit better our current practice. GVHD and relapse free survival (GRFS) have recently been reported in the context of hematological malignancies, as a surrogate marker of quality of survival (Holtan et al. blood 2014). However, this end point was not evaluated in the setting of SAA, with no need of GVT effect, but more concern regarding engraftment. Thus, we adapted from Holtan et al. a composite GRFS with the aim to provide more accurate evaluation of outcome after HSCT for SAA. Methods: We analyzed adult pts undergoing first HSCT for SAA from a MRD or 10/10 MUD between 2004 and 2013 (Clinical data obtained throughProMISe [Project Manager Internet Server], an internet-based system shared by SFGM-TC centers). Informed consent was obtained in accordance with the Declaration of Helsinki. Relevant events for GRFS were death, graft failure/loss, grade 3 to 4 acute GVHD and severe chronic GVHD, according to which one occurred first. We analyzed GRFS according to donor type. Moreover, prediction by dynamiclandmarkingwas used for continual reassessment of GRFS within the next 2 years following subsequent landmark times from 0 to 3 years after HSCT. Results: 188 pts (MRD, n=142; MUD n=46) with a median age of 30 years (18-67) were analyzed. After a median follow-up of 52 months (3-159), 2-year GRFS were 75% and 54% in pts receiving MRD and MUD HSCT, respectively (p=0.006, Figure 1A). In Causes of GRFS failure in MRD vs. MUD were grade 3-4 acute GVHD (5% vs 20%, p=0.002), extensive chronic GVHD (3% vs 4%, p=0.902), graft failure/loss (10% vs 4%, p=0.236) and death before the previous events (7% vs 18%, p=0.057). The use of peripheral blood graft (PBSC) was associated with lower 2-GRFS compared to bone marrow (51% vs 74%, p=0.004). Multivariate Cox model showed that MUD (p 〈 0.001), age (continuous variable, p=0.001) were associated with worse GRFS, with a significant interaction between these both variables (interaction p-value: 0.008, Figure 1B). PBSC as graft source (p=0.096) and positive donor and/or recipient CMVsero-status (p=0.095) tended to decrease GRFS. Although the pts in the MUD group initially have worse overall GRFS, prediction by dynamiclandmarkingshowed that after 6 months post HSCT, they recovered the same GRFS as those transplanted with MRD. Indeed, the probabilities to stay event-free within 2 years following the 6-month landmark time was 89% and 86% in the MRD and MUD groups, respectively (Figure 2). Conclusion: GRFS after MRD HSCT is very good, with 75% of pts who did not present any events, supporting upfront HSCT for young patients with available MRD. In contrast, the higher incidence of acute GVHD (20% vs. 5%) after MUD significantly decreased GRFS compared to MRD. However, MUD pts surviving the early 6 months without may reach similar GRFS than pts transplanted with MRD. Taken together, these results suggest that although overall GRFS is good with low incidence of late events, early events such as acute GVHD remains a major cause of GRFS failure. This supports that the early post HSCT period remains a critical phase for the future good quality survival, underlining the importance of graft source choice as well as the need of GVHD prophylaxis improvement. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Peffault de Latour: Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Abstract: Background: Nowadays acute myeloid leukemia (AML) patients above the age of 60 years are often candidates for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). However, little is known about the outcomes of HSCT in this particular population, due to the low number of HSCT with robust follow-up, the heterogeneity between centers, as well as reports usually mixing AML and other diseases such as myelodysplastic syndrome. We used the database of the Francophone society for stem cell transplantation and cellular therapy to address this question in a large cohort of patients in a recent time period. Patients and methods: 1167 consecutive patients aged ≥60 years with AML in complete remission (CR), transplanted between January 1st 2006 and January 1st 2016, reported to ProMISe (Project Manager Internet Server), an internet-based system shared by 36 Francophone transplantation centers, were reviewed. Classical post-HSCT endpoints were studied such as engraftment, acute and chronic graft-versus-host disease (GvHD), non-relapse mortality (NRM), relapse rate, leukemia free survival (LFS) as well as overall survival (OS). Cytogenetic risk was assessed according to the European Leukemia Network 2017 for patients in first complete remission. Data were analyzed using proportional hazards models and proportional sub-distribution hazards models in presence of competing risks. Results: Patients' Characteristics are detailed in Table 1. The median age at HSCT was 62.9 years (Interquartile range -IQR 61.9-66.1). Patients aged ≥60 years but less of 65 represented 63.8% of the population with 68.2% of patients transplanted in the recent period (2011-2016). Most patient had de novo AML (91.6%), in first CR (76.9%) with intermediate risk (83.8%) according to ELN-2017 classification. A matched unrelated donor (MUD) was used in 45 % of transplants and the majority of patients received peripheral blood stem cells (83.7%). Half of the patients received fludarabine and 2 days busulfan as conditioning regimen. The majority of patients (70.9%) received anti-thymocyte globuline (ATG). Engraftment occurred in 1089 patients (93.3%; 95%CI, 91.9-94.8). Day 100 cumulative incidence of grade II-IV acute GVHD was 24.6% (15.7% grade II; 5.8% grade III; 3% grade IV). At last follow up, 378 patients had developed chronic GVHD (severe in 37.2% of them; 95%CI, 34.0-40.3). With a median follow-up of 3.5 years (95%CI, 3.1-3.7 years), overall survival (OS) and LFS probabilities at 3 years were 50.7% (95%CI, 47.7-54.0) and 44.8% (95%CI, 41.8-48.1), respectively. In multivariable analysis, the only factor associated with worse OS was the use of a mismatched unrelated donor compare to MUD [Hazard Ratio (HR): 1.35 (95% CI, 1.01 to 1.80), p=0.04]. At 3 years, relapse incidence was 34.4% (95% CI, 31.5-37.4). The use of a sibling donor compared to MUD [Sub-distribution Hazard Ratio (SHR): : 1.49 (95% CI, 1.19 to 1.87), p 〈 0.001], poor risk AML in CR1 according to ELN classification [SHR: 1.49 (95% CI, 1.10 to 2.02), p=0.01] , as well as the use of ATG in the conditioning regimen [SHR: 1.57 (95% CI, 1.21 to 2.05), p 〈 0.001] were associated with a higher risk of relapse. During the study, 534 patients died (main causes of death was relapse, 53%); leading to a CI of NRM of 20.7% at 3 years (95%CI, 18.2-23.2). A karnofsky score above 90% [SHR: 0.74 (95% CI, 0.56 to 0.98), p=0.04] and the use of a sibling donor compare to MUD [SHR : 0.43(95% CI, 0.30 to 0.63), p 〈 0.001] were associated with reduced NRM. Conclusion: With more than 3 years follow-up, which is long enough for our results to be considered to be robust, the use of a mismatched unrelated donor was the only factor associated with worse overall survival in this population of AML patients aged of 60 years or more. Relapse appeared as the first cause of death, independently related to AML ELN poor risk classification, but also to the use of a sibling donor and of ATG in the conditioning regimen. This study highlights the major role of alloreactivity in this particular population, where modulation of T-cell alloreactivity as well as donor choice should be urgently addressed in well-designed prospective trials. Disclosures Peffault De Latour: Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.